rs3740281

Positions:

• chr10-89012393-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000043.6(FAS):​c.651+312G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.124 in 310,070 control chromosomes in the GnomAD database, including 2,886 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.11 (1195 hom., cov: 32)
  • Exomes 𝑓: 0.14 (1691 hom.)
• Consequence: FAS NM_000043.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.222

Genes affected

FAS (HGNC:11920): (Fas cell surface death receptor) The protein encoded by this gene is a member of the TNF-receptor superfamily. This receptor contains a death domain. It has been shown to play a central role in the physiological regulation of programmed cell death, and has been implicated in the pathogenesis of various malignancies and diseases of the immune system. The interaction of this receptor with its ligand allows the formation of a death-inducing signaling complex that includes Fas-associated death domain protein (FADD), caspase 8, and caspase 10. The autoproteolytic processing of the caspases in the complex triggers a downstream caspase cascade, and leads to apoptosis. This receptor has been also shown to activate NF-kappaB, MAPK3/ERK1, and MAPK8/JNK, and is found to be involved in transducing the proliferating signals in normal diploid fibroblast and T cells. Several alternatively spliced transcript variants have been described, some of which are candidates for nonsense-mediated mRNA decay (NMD). The isoforms lacking the transmembrane domain may negatively regulate the apoptosis mediated by the full length isoform. [provided by RefSeq, Mar 2011]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.156 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FAS	NM_000043.6	c.651+312G>A		intron_variant		ENST00000652046.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAS	ENST00000652046.1	c.651+312G>A		intron_variant			NM_000043.6	A2

Frequencies

GnomAD3 genomes AF: 0.110 AC: 16759 AN: 151908 Hom.: 1198 Cov.: 32

Gnomad AFR AF: 0.0272

Gnomad AMI AF: 0.129

Gnomad AMR AF: 0.103

Gnomad ASJ AF: 0.138

Gnomad EAS AF: 0.00770

Gnomad SAS AF: 0.106

Gnomad FIN AF: 0.176

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.159

Gnomad OTH AF: 0.112

GnomAD4 exome AF: 0.137 AC: 21683 AN: 158046 Hom.: 1691 AF XY: 0.135 AC XY: 11617 AN XY: 85884

Gnomad4 AFR exome AF: 0.0308

Gnomad4 AMR exome AF: 0.100

Gnomad4 ASJ exome AF: 0.133

Gnomad4 EAS exome AF: 0.00538

Gnomad4 SAS exome AF: 0.113

Gnomad4 FIN exome AF: 0.168

Gnomad4 NFE exome AF: 0.161

Gnomad4 OTH exome AF: 0.131

GnomAD4 genome AF: 0.110 AC: 16747 AN: 152024 Hom.: 1195 Cov.: 32 AF XY: 0.108 AC XY: 8053 AN XY: 74298

Gnomad4 AFR AF: 0.0271

Gnomad4 AMR AF: 0.103

Gnomad4 ASJ AF: 0.138

Gnomad4 EAS AF: 0.00791

Gnomad4 SAS AF: 0.105

Gnomad4 FIN AF: 0.176

Gnomad4 NFE AF: 0.159

Gnomad4 OTH AF: 0.111

Alfa AF: 0.137 Hom.: 210

Bravo AF: 0.0999

Asia WGS AF: 0.0480 AC: 169 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	7.2
DANN	Benign	0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs3740281; hg19: chr10-90772150;